In the biopharmaceutical industry, increasingly, single-use or disposable containers or flexible bags are used. Such containers can be flexible or collapsible plastic bags that are supported by an outer rigid structure such as a stainless steel shell, the support structure also referred to herein as a “vessel.” Use of sterilized disposable bags eliminates the time-consuming step of cleaning the steel bioreactor and reduces the chance of contamination. Combining the single-use or disposable bags with a magnetically coupled agitator system establishes a sterile environment that is especially important for biopharmaceutical manufacturing.
Currently available single-use bioreactors utilize hose barb or similar fittings that are welded to the bag film as entry and exit points for conveyance of fluid. The fitting for a drain line on a bioreactor is typically located at the bottom of the bag. The drain line fitting generally has a tubular portion that is commonly described as a “dead-leg,” because it is a one-way fluid flow system. Media flows into the dead-leg portion of the fitting, where media, cells and other fluid components can settle and remain isolated from the bulk bioreactor environment. When cells collect in this portion of the fitting, they are generally deprived of nutrients, die, and release toxic compounds that can be detrimental to the growth and production of cells in the bulk culture. At present there is no effective means for preventing or completely eliminating this isolated volume of fluid and cells in a dead-leg portion of a drain fitting.
Currently available valves that are employed on single-use bioreactors include a non-invasive pinch valve, comprising flexible plastic or rubber tubing placed inside a valve body and a clamp or other means for pinching the tubing in order to close the channel in the tubing.
Another type of valve includes flexible tubing placed inside a valve body, and a plunger arranged to be forced down through the channel in the tubing to restrict flow. There are disadvantages associated with these currently available valves. For example, the rubber or plastic tubing over time becomes fatigued from constant compression or from curing of the polymer material, leading to breakage and/or particle generation. Either of these can be detrimental to bioprocessing by either contaminating the culture or by generating particles that will flow into the bulk fluid. Another type of valve is an in-line fitting to which tubing is connected, the valve including a ball with a hole therethrough, such that in one position the flow path is open, and if rotated 90 degrees the flow path is closed.
Another on-going problem related to the use of single-use flexible or semi-rigid bioreactor bags is that many chemical, biological or pharmaceutical manufacturing processes are preferably conducted at pressures significantly above or below atmospheric pressure. Such processes have typically required rigid vessels, such as stainless steel bioreactors, that can withstand high positive or negative pressures. Flexible wall disposable single-use manufacturing systems, on the other hand, typically have limited capability of withstanding relatively high pressures. In addition, installing flexible containers or wall liners in pressurizable support structures can lead to difficulties in loading and unloading the disposable component from the system. The pressurizable support structure requires openings large enough to insert and remove the disposable reactant container easily. Consequently, lids, seals and fasteners must be designed to cover such openings so that they are strong enough to withstand the forces involved. As the size of the vessels increases, the ergonomics of bag unloading and loading worsen and the heavier vessel hardware becomes more complicated to operate.
Thus there is a currently unmet need for both non-dead leg valves for use in single-use, flexible bioreactor containers and for high performance flexible containers for use in pressurized biological manufacturing processes.